7-Hydroxy-benzo[ij]quinolizine-2-carboxylic acids and derivatives thereof

ABSTRACT

Certain substituted 6,7-dihydro-7-hydroxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acids and salt and ester derivatives thereof are described. These compounds are useful antibacterial agents.

BACKGROUND OF THE INVENTION

This invention relates to derivatives of the heterocyclic system knownas benzo[ij]quinolizine. A further aspect of the invention relates tothe use of the compounds as antimicrobial agents. Pharmaceuticalcompositions containing the compounds are also included within the scopeof the invention.

DESCRIPTION OF THE PRIOR ART

The compound 6,7-dihydro-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylicacid and various derivatives thereof, including ester and saltderivatives, and disclosed in U.S. pat. application Ser. No. 303,254filed Nov. 2, 1972, as having antimicrobial activity. That disclosureincludes other compounds having similar activity in which the benzo ringportion of the molecule is substituted by a variety of substituents inthe 8, 9 and 10 positions, and the alicyclic ring is substituted bymethyl, ethyl, or trifluoromethyl groups. These compounds do not containany functional substituents on the alicyclic ring.

DESCRIPTION OF THE INVENTION

This invention relates to certain6,7-dihydro-7-hydroxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacids and ester and salt derivatives thereof. These compounds havingutility as antimicrobial agents. The structure and numbering system ofthe heterocyclic system of these compounds are ##SPC1##

Compounds of the invention are defined by the formula ##SPC2##

Wherein R¹ is hydrogen, methyl, or ethyl; R² is methyl, ethyl, methoxy,halogen, hydroxy, nitro, amino, acetamido or formamido; n is zero, oneor two, and when n is 2, R² may be methylenedioxy ##STR1## orethylenedioxy ##STR2## bonded to adjacent carbon atoms; and when R² isethyl, methoxy, nitro, amino, acetamido or formamido, and n is 2, eachR² must be different; and lower alkyl esters and pharmaceuticallyacceptable salt derivatives of said acids.

The terms "lower alkyl", "alkyl" or the abbreviation "alk" as usedherein refers to straight and branched-chain alkyl groups having 1 to 4carbon atoms.

It is well known in the art that pharmaceutically acceptable salts suchas alkali metal, alkaline earth, aluminum, iron, and other metal andamine salts can be readily formed from biologically active acids. Thesesalts are essentially equivalent to the acids with respect to biologicalactivity, and in some respects may even offer advantages over the acidsin absorption, formulation and the like due to their increased watersolubility.

Salts of the free acid compounds of the invention are prepared byreacting the corresponding acid with a base and evaporating to dryness.Inorganic bases or organic bases such as sodium methoxide or an aminemay be used. Presently preferred salts are alkali metal and alkalineearth salts.

The free acid compounds of the invention are preferred in that theyexhibit the highest levels of antimicrobial activity.

The lower alkyl esters and salts of the acid compounds are useful asintermediates for the preparation of the corresponding acids, and inmany cases these esters and salts are also useful as antimicrobialagents. The preferred esters are ethyl esters.

Compounds of formula 1 wherein R¹ is methyl or ethyl represent apreferred subclass of antimicrobial agents. Also preferred are compoundswherein n is one and R² is halogen, methyl, methoxy or hydroxy. When R²is halogen, it is preferably fluorine, chlorine or bromine. Anotherpreferred subclass of compounds is that wherein n is two and R² ismethylenedioxy or ethylenedioxy bonded to adjacent carbon atoms.

Compounds of formula 1 wherein R² is nitro or amino are particularlyuseful as intermediates for the preparation of other compounds of theinvention.

All compounds of formula 1 will have at least one optically activecenter at the 7-position. Compounds wherein R¹ is methyl or ethyl havean additional optically active center. Thus, compounds of the inventionmay have up to four or more optical isomers. Pure optical isomers of thecompounds may be synthesized, but the process is tedious andeconomically impractical using presently available techniques. Althoughit has been found that in some cases, one isomer may have moreantimicrobial activity than another, sufficient activity is obtainedwith a compound containing a mixture of isomers so as to make isolationof the individual isomers unnecessary. Since the acid compounds of theinvention have a reactive hydroxyl group in the 7-position and areactive acid group, they have potential utility as monomers for makingcertain polyesters.

The antimicrobial activity of the compounds of the invention can bedemonstrated by the known, standard plate dilution method for bacterialsusceptibility to antibiotics. (See English Antibiot. Chemother, Vol. 1,118, 1951.) The culture medium employed permits susceptibility testingof fastidious microorganisms toward antibiotics, sulfonamides, and otherchemotherapeutic agents. Tryptone soy agar (oxoid) of the followingcomposition is the culture medium.

    ______________________________________                                        Oxoid tryptone          15 g                                                  Oxoid soy peptone        5 g                                                  Sodium chloride          5 g                                                  Oxoid agar-agar No. 3   15 g                                                  Water                    1 liter                                              ______________________________________                                    

Using this test, the compounds of the invention have been found to havea broad spectrum of activity against gram-positive and gram-negativemicroorganisms.

The compounds of the invention are active against microorganisms eitherin the absence or presence of 10 percent horse serum.

In the test procedure the amount of a compound required to givecomplete, partial, or no inhibition of microbial growth on the agarplates is determined. The compound selected for evaluation is added tothe agar medium to give concentrations of one, 10 and 100 millligramsper liter. A series of plates is prepared with these concentrations, andeach series includes control plates containing only agar. Ten percenthorse serum is added to one series of such plates. Aliquots of brothculture of each of 11 species of microorganisms are innoculated onto theplates. The plates are incubated at 37° C in a ten percent carbondioxide atmosphere for 18 to 24 hours. The microbial growth on eachplate is read visually, and minimal inhibitory concentrations arerecorded.

The microorganisms for this test were:

1. Stapylococcus aureus

2. Bacillus subtilus

3. Pseudomonas aeruginosa

4. Escherichia coli

5. Streptococcus sp. *

6. Aspergillus niger

7. Candida albicans

8. Mima polymorpha

9. Herellea vaginicola

10. Klebsiella pneumoniae

11. Streptococcus fecaelis

Some of the compounds of the invention have also shown activity towardanaerobic bacteria, e.g., Bacteroides sp. and Clostridium welchii.

It will be understood by those skilled in the art that the species usedare representative indicator species, as it would be impractical toscreen against all bacteria. It is well known in the art that broadspectrum activity can be predicted on the basis of activity shownagainst selected representative bacterial species.

The compounds of the invention are active against microorganisms invitro or topically. In vitro activity is useful in itself sinceantimicrobial agents may be used as components of disinfecting solutionsfor disinfecting items such as medical and dental equipment. Thepreferred compounds of the invention are also active in vivo in animals.

Many of the compounds of the invention are active when administeredorally to animals. They are excreted in the urine, and are useful intreating urinary tract bacterial infections in mammals. An advantage ofthe compounds is that they appear to be conjugated to a minimal degreeby the mammalian organism. Because the compounds are not significantlyinactivated by normal metabolic processes, higher levels of the activeforms of the compounds can be maintained in the blood and urine.

The acute oral toxicity of the preferred compounds of the invention isgenerally moderate to low compared with the effective oral dose, andthey have a fair to excellent therapeutic ratio.

Presently preferred compounds of the invention have a broad spectrum ofantimicrobial activity and a good therapeutic ratio (LD₅₀ /ED₅₀).

These compounds are:

9-chloro-6,7-dihydro-7-hydroxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid;

6,7-dihydro-9-fluoro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylicacid;

9-chloro-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylicacid;

6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid;

6,7-dihydro-5,9-dimethyl-7-hydroxy-1-oxo-1H,5H-benzo[ij]-quinolizinecarboxylic acid;

6,7-dihydro-9-methoxy-5-methyl-7-hydroxy-1-oxo-1H,5H-benzo-[ij]quinolizine-carboxylicacid; and

6,7-dihydro-5,8-dimethyl-7-hydroxy-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylicacid.

The acidic compounds of the invention are ordinarily white or yellowishto brown crystalline or amorphous materials when purified. They aresubstantially insoluble in water, lower alcohols or hydrocarbons and aremore soluble in halogenated solvents and dimethylformamide and the like.The esters are generally somewhat more soluble in organic solvents. Thealkali metal salts have appreciable solubility in water and loweralcohols.

The compounds of the invention may be formulated by incorporating theminto conventional pharmaceutical carrier materials, either organic orinorganic, which are suitable for oral or intraperitoneal application.For in vitro or topical use, simple aqueous solutions or suspensions aremost conveniently employed. For this purpose, concentrations of theorder of 100 parts per million up to about 5 parts per thousand aresuitable. The formulation is used by immersing objects to be treatedtherein, or by local application to an infected area.

The amount of compound to be used, for example, in the treatment of amicrobial urinary infection by oral administration, will be an effectiveamount less than a toxic amount. The amount to be administered tocontrol an infection will depend upon the species, sex, weight andphysical condition of the patient as well as other variable factors.This judgment is well within the skill of the medical practitioner.Usually the amount will be less than 100 mg/kg per dose. Convenientlythis dose is administered in the form of conventional pharmaceuticalpreparations such as capsules, tablets, emulsions, solutions and thelike. Excipients, fillers, coatings, etc. are employed with tablets orcapsules, as is well known in the art.

Compounds of the invention are required to contain the functional andreactive hydroxy group in the 7-position of the heterocyclic system.These 7-hydroxy compounds must be prepared from the corresponding novel7-oxo compounds which are prepared from known starting materials throughan extended and complex synthetic sequence. Several novel types ofintermediates are formed during this sequence.

DESCRIPTION OF THE DRAWINGS

Understanding of the synthesis of compounds of the invention will befacilitated by reference to the accompanying drawings wherein sequence Ashows the preparation of compounds of the invention wherein R¹ is methylor ethyl, and sequence B shows the preparation of compounds wherein R¹is hydrogen.

In step 1 of sequence A, an aniline, substituted by the appropriate R²group or groups, is condensed with a dialkyl alkoxymethylenemalonatesuch as diethyl ethoxymethylenemalonate by heating at 120° to 150° C.The intermediate formed is condensed by heating at a temperature of 150°to 300° C. in a high boiling inert solvent such as diphenyl ether ormixtures of diphenyl ether and biphenyl (e.g. Dowtherm A) to give theethyl 4-hydroxyquinoline-3-carboxylate product of step 1.

Step 2 of sequence A is the saponification of the ester product ofstep 1. This step is successfully carried out using, e.g., aqueousalkali metal hydroxides such as sodium or potassium hydroxide.

The free acid product of step 2 is decarboxylated in step 3 of sequenceA, e.g. by heating in an inert high boiling solvent such as diphenylether. The product formed is a substituted 4-hydroxyquinoline.

Step 4 of sequence A is the reaction of phosphorous oxychloride with the4-hydroxyquinoline product of step 3 in an inert solvent to givereplacement of the hydroxy group by chlorine. In step 5 of sequence A,the 4-chloro substituent is replaced by an alkoxy group such as methoxyby reaction with methanolic sodium methoxide to provide the substituted4-methoxyquinoline intermediate. The hydroxy group is thereby blockedand protected from reaction with the alkyl lithium during the next stepof the reaction.

In step 6 of sequence A, the 4-methoxyquinoline intermediate is reactedwith methyl or ethyl lithium to give a methyl or ethyl substitution inthe 2-position. This reaction is carried out carefully under dryconditions in an inert solvent such as diethyl ether or tetrahydrofuran,generally at temperatures of -30° to 0° C. In the second part of thisstep the alkoxy group is converted back to hydroxy by acidic hydrolyticcleavage. The product is shown as its tautomeric form, a novelsubstituted 2-alkyl-4-oxo-1,2,3,4-tetrahydroquinoline.

Step 1 of sequence B is a known cyclization reaction described forexample, in the Journal of Organic Chemistry 28, 1134 (1963), andcomprises reacting a 2-anilinopropionic acid with polyphosphoric acid ata temperature of 110° to 130° C. This reaction provides knownintermediates which are 4-oxo-1,2,3,4-tetrahydroquinolines and R¹ ishydrogen. Steps 2-5 of sequence B are identical to steps 8-11,respectively of sequence A.

In step 7 of sequence A (step 2 of sequence B), the4-oxo-1,2,3,4-tetrahydroquinoline intermediate is heated with a dialkylalkoxymethylenemalonate such as diethyl ethoxymethylenemalonate at 130°to 200° C. to effect a condensation and provide a novel N-substitutedtetrahydroquinoline intermediate. This intermediate is condensed in step8 (step 3 of sequence B) by heating in the presence of polyphosphoricacid at 100° to 140° C to provide a novel alkyl6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylateintermediate.

The ester intermediate obtained in step 8 is saponified in step 9 (step4 of sequence B) using, for example, an aqueous alkali metal hydroxidesuch as sodium or potassium hydroxide, to provide the novel intermediateacid.

The 7-oxo group is reduced in step 10 (step 5 of sequence B) using aselective metal hydride reducing agent, preferably sodium borohydride.

The compounds of formula I wherein R² is nitro are readily prepared bynitration of other compounds of formula I. These nitro compounds may bereduced using e.g., iron and hydrochloric acid, hydrogen and Raneynickel or platinum on charcoal to prepare compounds wherein R² is amino.Compounds of formula I wherein R² is amino react with acetic anhydrideor formic acid to provide compounds wherein R² is acetamido orformamido, respectively.

Compounds of formula I wherein R² is methoxy are reacted in hydrobromicacid to provide compounds wherein R² is hydroxy. One class of novelintermediates formed during the process of synthesizing the finalproducts of the invention is represented by the formula ##SPC3##

wherin alk is an alkyl radical having 1 to 4 carbon atoms.

A second class of novel intermediates of the invention may berepresented by the formula ##SPC4##

wherein R³ is hydrogen or lower alkyl.

The following non-limiting examples are provided to illustrate thecompounds of the invention and the synthetic methods used to obtainthem.

EXAMPLE 1 -- STEP 1

A mixture of 66.6 g (0.6 mole) of 4-fluoroaniline and 129.79 g (0.6mole) of diethyl ethoxymethylenemalonate was prepared under a nitrogenatmosphere and heated to 140° C. The ethanol generated was allowed tovaporize during a reaction time of about one hour. To the mixture wasadded 500 ml of diphenyl ether. The mixture was stirred and heated toits reflux temperature, and maintained at reflux for 15 minutes. Themixture was then cooled, and diethyl ether was added. The product wasseparated by filtration, washed with diethyl ether and air dried toprovide 97.3 g (69% yield) of ethyl6-fluor-4-hydroxyquinoline-3-carboxylate.

EXAMPLE 2 -- STEP 2 AND 3

A mixture of 94 g (0.4 mole) of ethyl6-fluoro-4-hydroxyquinoline-3-carboxylate from example 1, 80 g (2.0mole) of sodium hydroxide and 200 ml of water was heated to its refluxtemperature and held at that temperature while stirring for 30 minutes.The hot solution was poured into a mixture of ice and hydrochloric acid.The acid solution was filtered, washed with water and suctioned dry. Thesolid obtained was dissolved in 200 ml of diphenyl ether, and thesolution heated to its reflux temperature and maintained at reflux forless than 5 minutes. After cooling for several hours the solidprecipitate was separated and washed with diethyl ether. The identity ofthe product, 6-fluoro-4-hydroxyquinoline, was confirmed by infrared andnuclear magnetic resonance spectral analyses.

EXAMPLE 3 -- STEP 4 AND 5

To a stirred solution of 62.5 g (0.383 mole) of6-fluoro-4-hydroxyquinoline from example 2 in 200 ml. of1,2-dichloroethane was added in small portions 88 g (0.575 mole) ofphosphorous oxychloride while maintaining the temperature at 30° to 40°C. The mixture was heated to its reflux temperature and maintained atreflux for 90 minutes.

The mixture was cooled, slurried in 500 ml of diethyl ether andfiltered, and the residue was washed with diethyl ether. The organicfiltrate was extracted twice with water. The residue was added to theaqueous extracts and the mixture was made basic and filtered. Theresidue was dissolved in chloroform. The chloroform solution was dried,filtered and evaporated in vacuo. The residue was slurried into hexaneand then filtered to provide 58 g (86% yield) of4-chloro-6-fluoroquinoline.

This intermediate was added to 0.4 mole of methanolic sodium methoxide.The mixture was heated to its reflux temperature and refluxed under anitrogen atmosphere for about 16 hours. The solution was cooled,filtered, and evaporated in vacuo. The residue was slurried with waterand extracted into diethyl ether. The ether extracts were dried andevaporated in vacuo to give 53.1 g (94% yield) of6-fluoro-4-methoxyquinoline.

EXAMPLE 4 -- STEP 6

A stirred solution of 25.8 g (0.146 mole) of 6-fluoro-4-methoxyquinolinefrom example 3 in 300 ml of tetrahydrofuran was heated under a nitrogenatmosphere to its reflux temperature and then cooled to -20° C. To thecold solution was added 90 ml of 182 M methyl lithium in diethyl etherover a period of 0.5 hour. After adding 40 ml of the solution, thereaction temperature was allowed to rise to 0° C. After the addition ofmethyl lithium was completed, the reaction temperature was allowed torise to 15° C. The solution was then poured into 1200 ml of a mixture ofice water and hydrochloric acid. After stirring for 0.5 hour the mixturewas extracted with about 1200 ml of diethyl ether. The organic layer wasdried, filtered and evaporated in vacuo to provide a yellow solid. Theproduct was recrystallized from carbon tetrachloride to give 9.5 g. (37%yield) of 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.

EXAMPLE 5 -- STEP 7 AND 8

A stirred mixture of 12 g (0.067 mole) of6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline from example 4 and14.8 g (0.070 mole) of diethyl ethoxymethylenemalonate was heatedgradually to 160° to 180° C. while removing the ethanol generated bydistillation. After 0.5 hour the mixture was cooled to 60° C., and 30 gof polyphosphoric acid was added. This mixture was heated gradually to150 to 160° C. and maintained at 155° to 160° C. for 5 to 10 minutes.Following cooling, water was added, and the mixture was kneaded toproduce an orange powder which was separated by filtration.Recrystallization from a mixture of 500 ml of 95% ethanol and 100 ml ofglacial acetic acid gave a yellow product, ethyl6,7-dihydro-1,7-dioxo-9-fluoro-5-methyl-1H,5H-benzo[ij]-quinolizine-2-carboxylate,m.p. 262°-265° C.

EXAMPLE 6 -- STEP 9

To a refluxing solution of 5.8 g (0.0191 mole) of ethyl6,7-dihydro-1,7-dioxo-9-fluoro-5-methyl-1H,5H-benzo[ij]-quinolizine-2-carboxylatefrom example 5 in 50 ml of acetic acid was added 50 ml of 6Nhydrochloric acid. After heating at reflux for one hour, the mixture wascooled, 100 ml of water added and the product separated by filtration.The yellow solid was6,7-dihydro-1,7-dioxo-9-fluoro-5-methyl-1H,5H-benzo[ij]quinolizine-2-carboxylicacid. Analysis: Calculated for C₁₄ H₁₀ FNO₄ : %C, 61.1; %H, 3.7; %N,5.1. Found: %C, 61.0; %H, 3.5; %N, 5.1.

EXAMPLE 7 - STEP 10

A solution of 2.8 g (0.01 mole) of9-chloro-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid from example 6 in 100 ml of water was prepared by suspending theacid in water, adding excess dilute sodium hydroxide and warming. Tothis solution was added 0.15 g (0.004 mole) of sodium borohydride, andthe mixture was stirred at room temperature for 6 hours. The mixture wasthen acidified with dilute hydrochloric acid and the solid productseparated by filtration. The product was washed successively with water,methanol and diethyl ether. The solid was recrystallized from an aceticacid-N,N-dimethylformamide mixture to provide 1.6 g of tan solid whichwas9-chloro-6,7-dihydro-7-hydroxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, m.p. >250° C. (yield 57%). Analysis: Calculated for C₁₃ H₁₀ CINO₄: %C, 55.8; %H, 3.6; %N, 5.0; Found: %C, 55.6; %H, 3.7; %N, 5.0.

The following examples illustrate other compounds of the invention whichwere prepared using the method of examples 1 to 7.

EXAMPLE 8

6,7-dihydro-9-fluoro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. Analysis: Calculatedfor C₁₄ H₁₂ FNO₄ : %C, 60.7; %H, 4.4; %N, 5.1; Found: %C, 60.7; %H, 4.2;%N, 5.0.

EXAMPLE 9

9-chloro-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >250° C.Analysis: Calculated for C₁₄ H₁₂ CINO₄ : %C, 57.2; %H, 41.1; %N, 4.8;Found: %C, 56.8; %N, 4.1; %H, 4.8.

EXAMPLE 10

6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid m.p. >250° C.Analysis: Calculated for C₁₄ H₁₃ NO₂₁ : %C, 64.9; %H, 5.1; %N, 5.4;Found: %C, 64.3; %H, 5.0; %N 5.2.

EXAMPLE 11

6,7-dihydro-5,9-dimethyl-7-hydroxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, m.p. >260° C. Analysis: Calculated for C₁₅ H₁₅ NO₄ : %C, 65.9; %H,5.5; %N, 5.1; Found: %C, 65.3; %H, 5.5; %N 4.9.

EXAMPLE 12

6,7-dihydro-9-methoxy-5-methyl-7-hydroxy-1-oxo-1H,5H-benzo[ij]quinolizine-carboxylicacid, m.p. >260° C. Analysis: Calculated for C₁₅ H₁₅ NO₅ : %C, 62.3; %H,5.2; %N, 4.8; Found: %C, 61.8; %H, 5.1; %N, 4.8

EXAMPLE 13

6,7-dihydro-5,8-dimethyl-7-hydroxy-1-oxo-1H,5H-benzo[ijquinolizine-2-carboxylic acid, m.p. >260° C. Calculated for C₁₅ H₁₅ NO₄: %C, 65.9; %H, 5.5; %N, 5.1; Found: %C, 65.6; %H, 5.4; %N, 4.9.

The following table I illustrates compounds of formula I which may beprepared from the starting materials shown by following the reductionstep of Example 7. The novel starting materials are prepared accordingto the synthetic method described in examples 1- 6. ##SPC5##

EXAMPLE 23

This example illustrates the preparation of compounds of formula 1wherein R² is nitro.

A solution of 0.1 mole of6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid in 150 ml. of concentrated sulfuric acid is treated with a mixtureof 150 ml. of concentrated sulfuric acid and 10 ml. of nitric acid whilekeeping the temperature below 30° C. The solution is stirred for about24 hours, poured over ice and partially neutralized to a pH of 2 withammonium hydroxide. The product,6,7-dihydro-7-hydroxy-5-methyl-10-nitro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid is isolated by filtration.

EXAMPLE 24

This example illustrates the preparation of compounds of formula Iwherein R² is amino.

6,7-dihydro-7-hydroxy-5-methyl-10-nitro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid (0.05 mole) is dissolved in 400 ml. of aqueous potassium hydroxideand hydrogenated on a Parr apparatus at an initial hydrogen pressure of50 psi using Raney nickel catalyst. The mixture is filtered, and thefiltrate is adjusted to a pH of 6 with hydrochloric acid. The product,10-amino-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, is separated by filtration.

EXAMPLE 25

This example illustrates the preparation of compounds of formula Iwherein R² is hydroxy and n is 2.

Starting with 3,5-dimethoxyaniline and following the method of examples1 to 7, one obtains6,7-dihydro-8,10-dimethoxy-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid. This intermediate (0.1 mole) is added to 250 ml. of hydrobromicacid and the mixture is heated at reflux for 6 hours. The mixture isdiluted with water and the resulting solid precipitate is separated byfiltration to give6,7-dihydro-5-methyl-1-oxo-7,8,10-trihydroxy-1H,5H-benzo[ij]quinolizine-2-carboxylicacid.

EXAMPLE 26

This example illustrates the preparation of compounds of formula Iwherein R² is acetamido.

10-amino-6,7-dihydro-5-methyl-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid (0.02 mole) and acetic anhydride (50 ml.) are stirred and heated ona steam bath for 3 hours. After cooling, the solid precipitate isseparated by filtration to give10-acetamido-6,7-dihydro-5-methyl-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid. This product is reduced using sodium borohydride to provide10-acetamido-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid.

EXAMPLE 27

This example illustrates the preparation of compounds of formula Iwherein R² is formamido.

A mixture of 25 ml. of formic acid and 0.2 mole10-amino-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid is heated at reflux for 2 hours. The solution is poured into waterand the product separated by filtration is6,7-dihydro-10-formamido-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid.

What is claimed is:
 1. A compound of the formula ##SPC6##wherein R¹ ishydrogen, methyl or ethyl; R² is methyl, ethyl, halogen, hydroxy, nitro,amino, acetamido or formamido; n is zero, one or 2, and when n is 2, R²may be methylenedioxy or ethylenedioxy bonded to adjacent carbon atoms;and when R² is ethyl, methoxy, nitro, amino, acetamido or formamido, andn is 2, each R² must be different; and lower alkyl ester orpharmaceutically acceptable salt derivatives thereof.
 2. A compoundaccording to claim 1 wherein R¹ is methyl or ethyl.
 3. A compoundaccording to claim 2 wherein n is one.
 4. A compound according to claim3 wherein R² is halogen, methyl or hydroxy.
 5. A compound according toclaim 4 wherein R² is fluorine, chlorine or bromine.
 6. The compound6,7-dihydro-9-fluoro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid according to claim
 5. 7. The compound9-chloro-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid according to claim
 5. 8. A compound according to claim 1 wherein nis 2 and R² is ethylenedioxy or methylenedioxy bonded to adjacent carbonatoms.